IQGAP1 scaffold-MAP kinase interactions enhance multiple myeloma clonogenic growth and self-renewal

Christian Gocke, Ross McMillan, Qiuju Wang, Asma Begum, Vesselin R. Penchev, Syed Abbas Ali, Ivan M Borrello, Carol Ann Huff, William Matsui

Research output: Contribution to journalArticle

Abstract

Despite improved outcomes in newly diagnosed multiple myeloma, virtually all patients relapse and ultimately develop drug-resistant disease. Aberrant RAS/MAPK signaling is activated in the majority of relapsed/refractory multiple myeloma patients, but its biological consequences are not fully understood. Selfrenewal, as defined by the long-term maintenance of clonogenic growth, is essential for disease relapse, and we examined the role of RAS/MAPK activation on multiple myeloma self-renewal by targeting IQ motif-containing GTPase-activating protein 1 (IQGAP1), an intracellular scaffold protein required for mutant RAS signaling. We found that loss of IQGAP1 expression decreased MAPK signaling, cell-cycle progression, and tumor colony formation. Similarly, a peptide mimicking the WW domain of IQGAP1 that interacts with ERK inhibited the clonogenic growth and self-renewal of multiple myeloma cell lines and primary clinical specimens in vitro as well as tumor-initiating cell frequency in immunodeficient mice. During multiple myeloma progression, self-renewal may be enhanced by aberrant RAS/MAPK signaling and inhibited by targeting IQGAP1.

Original languageEnglish (US)
Pages (from-to)2733-27339
Number of pages24607
JournalMolecular Cancer Therapeutics
Volume15
Issue number11
DOIs
StatePublished - Nov 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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